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Trialkyltin Compounds Bind Retinoid X Receptor to Alter Human Placental Endocrine Functions

Department of Toxicology (T.N., Y.H., H.Y., M.K., S.T., J.I., M.W., S.I., N.I., K.T.) and Laboratory of Environmental Biochemistry (J.N., T.N.), Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871; Laboratory of Pharmaceutics (N.U.), School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195; and Development Division (Y.K.), Fujisawa Pharmaceutical Co., Ltd., Osaka 532-8514, Japan

Address all correspondence and requests for reprints to: Dr. Tsuyoshi Nakanishi, Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1–6, Yamadaoka Suita, Osaka 565-0871, Japan. E-mail: nakanishi{at}phs.osaka-u.ac.jp.

Retinoid X receptor (RXR) is a nuclear receptor that plays important and multiple roles in mammalian development and homeostasis. We previously reported that, in human choriocarcinoma cells, tributyltin chloride and triphenyltin hydroxide, which are typical environmental contaminants and cause masculinization in female mollusks, are potent stimulators of human chorionic gonadotropin production and aromatase activity, which play key endocrine functions in maintaining pregnancy and fetal development. However, the molecular mechanism through which these compounds stimulate these endocrine functions remains unclear. Our current study shows that trialkyltin compounds, including tributyltin chloride and triphenyltin hydroxide, function as RXR agonists. Trialkyltins directly bind to the ligand-binding domain of RXR with high affinity and function as transcriptional activators. Unlike the natural RXR ligand, 9-cis-retinoic acid, the activity of trialkyltins is RXR specific and does not activate the retinoic acid receptor pathway. In addition, trialkyltins activate RXR to stimulate the expression of a luciferase reporter gene containing the human placental promoter I.1 sequence of aromatase, suggesting that trialkyltins stimulate human placental endocrine functions through RXR-dependent signaling pathways. Therefore, our results suggest that activation of RXR may be a novel mechanism by which trialkyltins alter human endocrine functions.

NURSA Molecule Pages Link:

Nuclear Receptors:   RXRα  |  RXRβ  |  RXRγ

Ligands:   LGD 100268  |  Am 580  |  9-cis-Retinoic acid  |  15-Deoxy-Δ12 14 prostaglandin  |  Rosiglitazone

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